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PMID:8573071
Citation |
Si-Tahar, M, Renesto, P, Falet, H, Rendu, F and Chignard, M (1996) The phospholipase C/protein kinase C pathway is involved in cathepsin G-induced human platelet activation: comparison with thrombin. Biochem. J. 313 ( Pt 2):401-8 |
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Abstract |
Cathepsin G, an enzyme released by stimulated polymorphonuclear neutrophils, and thrombin are two human proteinases which potently trigger platelet activation. Unlike thrombin, the mechanisms by which cathepsin G initiates platelet activation have yet to be elucidated. The involvement of the phospholipase C (PLC)/protein kinase C (PKC) pathway in cathepsin G-induced activation was investigated and compared with stimulation by thrombin. Exposure of 5-[14C]hydroxytryptamine-labelled platelets to cathepsin G, in the presence of acetylsalicylic acid and phosphocreatine/creatine kinase, induced platelet aggregation and degranulation in a concentration-dependent manner (0.1-3.0 microM). Time-course studies (0-180 s) comparing equivalent concentrations of cathepsin G (3 microM) and thrombin (0.5 unit/ml) resulted in very similar transient hydrolysis of phosphatidylinositol 4,5-bisphosphate and steady accumulation of phosphatidic acid. In addition cathepsin G, like thrombin, initiated the production of inositol phosphates. The neutrophil-derived proteinase also induced phosphorylation of both the myosin light chain and pleckstrin, a substrate for PKC, to levels similar to those observed in platelets challenged with thrombin. Inhibition of PKC by GF 109203X, a specific inhibitor, suppressed platelet aggregation and degranulation to the same extent for both proteinases. Using fura 2-loaded platelets, the rise in the cytosolic free Ca2+ concentration induced by cathepsin G was shown to result, as for thrombin, from both mobilization of internal stores and Ca2+ entry across the plasma membrane. These findings provide evidence that cathepsin G stimulates the PLC/PKC pathway as potently as does thrombin, independently of thromboxane A2 formation and ADP release, and that this pathway is required for platelet functional responses. |
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Keywords |
Amino Acid Sequence; Blood Platelets/metabolism; Calcium/metabolism; Cathepsin G; Cathepsins/physiology; Enzyme Activation; Humans; Molecular Sequence Data; Phospholipids/metabolism; Phosphorylation; Platelet Activation/physiology; Protein Kinase C/metabolism; Serine Endopeptidases; Serotonin/metabolism; Thrombin/physiology; Type C Phospholipases/metabolism |
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Significance
Annotations
Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
---|---|---|---|---|---|---|---|---|
GO:0006468: protein phosphorylation |
ECO:0000314: |
P |
Figure 4 Time course of protein phosphorylation in platelets challenged with cathepsin G or thrombin. |
complete | ||||
GO:0030168: platelet activation |
ECO:0000314: |
P |
Fig 1,2. Figure 5 Effect of GF 109203X on platelet activation induced by cathepsin G or thrombin. |
complete | ||||
involved_in |
GO:0006468: protein phosphorylation |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
See also
References
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